rs61749721
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001110792.2(MECP2):c.799C>T(p.Arg267Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
MECP2
NM_001110792.2 stop_gained
NM_001110792.2 stop_gained
Scores
3
2
3
Clinical Significance
Conservation
PhyloP100: 2.35
Genes affected
MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.466 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-154031065-G-A is Pathogenic according to our data. Variant chrX-154031065-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031065-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MECP2 | NM_001110792.2 | c.799C>T | p.Arg267Ter | stop_gained | 3/3 | ENST00000453960.7 | NP_001104262.1 | |
| MECP2 | NM_004992.4 | c.763C>T | p.Arg255Ter | stop_gained | 4/4 | ENST00000303391.11 | NP_004983.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MECP2 | ENST00000453960.7 | c.799C>T | p.Arg267Ter | stop_gained | 3/3 | 1 | NM_001110792.2 | ENSP00000395535 | ||
| MECP2 | ENST00000303391.11 | c.763C>T | p.Arg255Ter | stop_gained | 4/4 | 1 | NM_004992.4 | ENSP00000301948 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:45Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Rett syndrome Pathogenic:22Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Breakthrough Genomics, Breakthrough Genomics | Feb 24, 2021 | This variant was previously reported in multiple unrelated individuals with Rett syndrome [PMID: 23270700, 21982064, 23810759,10508514, 17089071] including several de novo observations. This variant was classified a pathogenic [PMID: 23810759] and reported to be associated with bone disease severity in subjects with Rett syndrome [ PMID: 32005172]. In-vitro functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and transcriptional repression [PMID: 23238081, 11058114]. In addition, mouse models harboring this variant recapitulates Rett syndrome-like phenotypes [PMID: 25634563, 32927061]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 20, 2015 | This nonsense variant is predicted to cause a truncated protein, which is commonly known mechanism for disease. Variant is absent from large and broad cohorts of the ExAC project while it has been reported in at least ten RTT patients. Many clinical labs and databases classify this variant as pathogenic. Functional studies showed that variant led to deficient transcriptional repression, decreased binding to methylated DNA, and impaired microtubule stability in astrocytes. Considering all, this variant has been classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 13, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 11, 2008 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 13, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Oct 01, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jun 15, 2017 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
| Pathogenic, criteria provided, single submitter | curation | Centre for Population Genomics, CPG | Jan 09, 2024 | This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4)(PP4). Is a common, recurrent pathogenic variant ,identified as a de novo occurrence in at least one individual with Rett syndrome (PM6).(PMID: 20301670 , ClinVar database Variation ID: 11829) - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 06, 2022 | - - |
| Pathogenic, criteria provided, single submitter | research | Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences | - | - - |
| Pathogenic, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Nov 18, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Jun 19, 2020 | This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.R255* in MECP2 (NM_004992.4) has been reported reported in many individuals affected with Rett syndrome, including several de novo observations (Olivia Knight et al 2013). Experimental studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and transcriptional repression (Chloe Delepine et al, 2013; T M Yusufzai wt al 2020). The variant has been reported in ClinVar as Pathogenic/Likely Pathogenic. The p.R255* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011829, PMID:10508514). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jul 15, 2015 | Developmental arrest; Repeated hand to mouth movements; Microcephaly; Seizures; Normal development to 6 months of age - |
| Pathogenic, no assertion criteria provided | case-control | Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 28, 2017 | A heterozygous nonsense variant was identified, NM_004992.3(MECP2):c.763C>T in exon 4 of the MECP2. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 255, NM_004992.3(MECP2):p.(Arg255*). Previous studies have shown that this results in loss of function through protein truncation (Yusufzai TM. et al, 2000). This variant is not present in the gnomAD population database and it has been previously reported multiple times in patients with Rett Syndrome (ClinVar). Additionally, functional studies showed that this variant causes loss of MECP2 transcription repression and DNA binding functions (Yusufzai TM. et al, 2000) and affects microtubule dynamics in astrocytes (Delépine C. et al,2013). Additionally, other truncating variants downstream of c.763C>T in MECP2 have been reported as pathogenic in individuals with this condition (ClinVar). Based on current information, this variant has been classified as PATHOGENIC. - |
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
not provided Pathogenic:12
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 25, 2020 | Published many times in association with both classic and atypical Rett syndrome (for examples, see Hoffbuhr et al., 2001; Yamada et al., 2001; Neul et al., 2008; Lima et al., 2009); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Functional studies indicate this variant affects the protein's ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31512412, 31535341, 31139143, 30829465, 31134136, 30536762, 29655203, 30564305, 28135719, 28399682, 28263302, 26175308, 16077729, 27824329, 19722030, 18337588, 11524741, 11402105, 23238081, 10508514, 11058114, 25634563, 21575601, 23270700, 18174548) - |
| Pathogenic, no assertion criteria provided | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Apr 03, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 27, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 17, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 10, 2021 | The MECP2 c.763C>T, p.Arg255Ter variant (rs61749721) induces an early termination codon and is predicted to result in a truncated protein or absent transcript. This variant is one of the most common disease causing variants of Rett syndrome (RTT) (Neul 2008), and has been associated with both classical and atypical RTT (see link to RettBASE and references therein). Functional studies showed p.Arg255Ter to be less stable in vivo and lead to deficient transcriptional repression (Yusufzai 2000). Furthermore, this variant is reported as pathogenic in ClinVar (Variation ID: 11829), and is absent from population databases (Exome Variant Server, Exome Aggregation Consortium). Therefore, this variant is considered to be pathogenic. REFERENCES Link to RettBASE: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Neul JL et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008; 70(16):1313-21. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 16, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 16, 2018 | The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Jan 10, 2022 | MECP2 NM_004992.3 exon 4 p.Arg255* (c.763C>T): This variant has been reported in the literature in numerous (n>100) individuals with Rett syndrome (select publications: Amir 1999 PMID:10508514, Knight 2013 PMID:23270700, McRae 2017 PMID:28135719, Hettiarachchi 2019 PMID:31535341, RettBASE). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:11829). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In addition, functional studies have shown a deleterious effect of this variant (Yusufzai 2000 PMID:11058114, Delepine 2013 PMID:23238081, Pitcher 2015 PMID:25634563). However, these studies may not accurately represent in vivo biological function. The vast majority of pathogenic variants are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain. This variant creates a premature stop at this codon within exon 4 which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Philippe 2006 16473305). In summary, this variant is classified as pathogenic based on the data above. - |
MECP2-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 08, 2024 | The MECP2 c.763C>T variant is predicted to result in premature protein termination (p.Arg255*). This variant has previously been reported to be causative for Rett Syndrome (Amir et al. 1999. PubMed ID: 10508514; Yusufzai et al. 2000. PubMed ID: 11058114; Pitcher et al. 2015. PubMed ID: 25634563) and it occurred de novo (Wang et al. 2019. PubMed ID: 31512412). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in MECP2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Loss-of-function variation in MECP2 is an established mechanism of disease (PMID: 22781840, 26942018, 31527487). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). The c.799C>T (p.Arg267Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic. - |
Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg255*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 232 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 1241840, 10508514, 17089071, 23270700). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11829). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 23238081, 25634563). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg270*) have been determined to be pathogenic (PMID: 11058114, 11241840, 18174548, 23238081). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Neurodevelopmental delay Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Syndromic X-linked intellectual disability Lubs type Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2023 | The c.763C>T (p.R255*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, results from a C to T substitution at nucleotide position 763. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 255. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts nearly half of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been detected in multiple individuals who meet classical clinical criteria for Rett syndrome and is a commonly reported nonsense mutation in the literature (Amir, 1999; Laccone, 2001; Li, 2007; Delépine, 2013). Based on the available evidence, this alteration is classified as pathogenic. - |
Abnormality of the nervous system Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | curation | RettBASE | Dec 05, 2013 | - - |
Autism Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Centre for Addiction & Mental Health, Centre for Addiction & Mental Health | - | Known mutation in known disease gene - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
MetaRNN
Pathogenic
D
MutationTaster
Benign
A;A;A
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at